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People with upper body or visceral obesity have a much higher risk of morbidity and mortality from obesity-related metabolic disorders than those with lower body obesity. In an attempt to develop therapeutic strategies targeting visceral obesity, depot- specific differences in the expression of genes in omental and subcutaneous adipose tissues were investigated by DNA array technology, and their roles in adipocyte differentiation were further examined. We found that levels of metallothionein-II (MT-II) mRNA and protein expression were higher in omental than in subcutaneous adipose tissues. The study demonstrates that MT-II may play an important role in adipocyte differentiation of 3T3L1 preadipocytes, and that N-acetylcysteine (NAC) inhibits the adipocyte differentiation of 3T3L1 cells by repressing MT-II in a time- and dose-dependent manner. Furthermore, the intraperitoneal administration of NAC to rats and mice resulted in a reduction of body weights, and a marked reduction in visceral fat tissues. These results suggest that MT-II plays important roles in adipogenesis, and that NAC may be useful as an anti-obesity drug or supplement.

The CDKN2 (MTS1/p16INK4A) gene, encoding cyclin dependent kinase inhibitor, was found to be homozygously deleted at a high frequency in cell lines from many different types of cancer and some primary cancers. To determine the frequency of CDKN2 mutations in most common human cancers in Korea, PCR and PCR-SSCP analyses for the exon 2 of CDKN2 were performed on each set of 20 formalin-fixed and paraffin-embedded tumor tissues of stomach adenocarcinomas, lung cancers, cervix cancers and hepatocellular carcinomas. No mutations in exon 2 of CDKN2 were found in 20 stomach adenocarcinomas. In contrast to rare mutations in stomach adenocarcinomas, a high frequency of CDKN2 mutations was identified in other 3 cancers, 11 of 20 (55%) lung cancers (7 of 10 NSCLCs and 4 of 10 SCLCs), 14 of 20 (70%) cervix cancers and 11 of 20 (55%) hepatocellular carcinomas. These results suggest that mutations of the CDKN2 gene might be an important genetic change in NSCLCs, cervix cancers and hepatocellular carcinomas.

The CDKN2 (MTS1/p16 INK4A ) and MTS2/p15 INK4B genes, encoding cyclin dependent kinase inhibitors, were found to be homozygously deleted at high frequency in cell lines from many different types of cancer and some primary cancers. To determine the frequency of CDKN2 and MTS2 mutations in human stomach, liver, and cholangio- cancers, molecular analyses of CDKN2 and MTS2 were performed on 4 stomach cancer cell lines, 14 primary stomach adenocarcinomas, 11 hepatocellular carcinomas, and 5 cholangiocarcinomas. Two (50%) of the four stomach cancer cell lines (SNU1, SNU5, SNU16 and Kato III) had mutations of the CDKN2 and MTS2 gene: SNU16, a homozygous deletion; SNU5, a nonsense mutation,CGA to TGA (Arg to stop) at codon 72 of the CDKN2 gene. No mutations were observed in the 14 primary stomach cancer tissues. In contrast to the mutations of CDKN2 and MTS2 , Northern blot analysis showed that expression of CDKN2 was absent or decreased in all the remaining four stomach cancer cell lines and 11 of the 14 (79%) primary stomach adenocarcino-mas. Five of the 11 (45%) hepatocellular carcinomas and one of the 5 (20%) cholangiocarcinomas have possible mutations in CDKN2 exon 2 and MTS2. One of hepatocellular carcinoma was expressed mobility shift on PCRSSCP analysis and a missense mutation, GAC to GAA (Asp to Glu) at codon 105 of CDKN2 gene. These results suggest that mutations or inacti-vation of the CDKN2 gene may be a critical genetic change in the formation of stomach, hepatocellular, and cholangiocarcinomas.

START (restriction) checkpoint in late G1 of the cell cycle is important in the regulation of cell proliferation. Many tumors have shown abnormalities partly in the components such as p53, proliferating cell nuclear antigen (PCNA), retinoblastoma protein (pRb), cyclin dependent kinase 4 (CDK4), cyclin D1 and cyclin dependent kinase inhibitors (CDIs) were involved in the START checkpoint. To determine the differential expression of p53, PCNA, CDK4 and pRb in most common human cancers in Korea, immunohistochemical analyses for these proteins were performed on each 20 formalin-fixed and paraffin-embedded tumor tissues of stomach adenocarcinomas, lung cancers, cervix cancers and liver cancers. Significant differences existed in the expression of the proteins among the cancers from different anatomic sites. Stomach adenocarcinomas (55%) and small cell lung cancers (SCLCs) (70%) had high rate of p53 overexpression. Overexpression of pRb was shown in 70% of stomach adenocarcinomas and 90% non small cell lung cancers (NSCLSs). SCLCs had the highest rate (80%) of pRb negativities. Cervix cancers showed the highest rate (60%) of CDK4 overexpression and lower rate (15%) of p53 overexpression. Liver cancers had the highest rate (90%) of PCNA overexpression and the lowest rate (10%) of p53 overexpression. Our results indicate that, at least, one of the abnormalities in p53, PCNA, CDK4 or pRb function occurs very commonly in these cancers, thereby, suggesting that components in restriction checkpoint play a critical role in the development of these cancers through functional inactivation of pRb.